tbuckley/cabot-search huggingface dataset:
Dapagliflozin associated to sacubitril/valsartan and relationship with cardioprotection in human cardiac cells exposed to doxorubicin and HER2-blocking agents through MyD88, NLRP3 mediated pathways.
Authors: Nicola Maurea, Vincenzo Quagliariello, Martina Iovine, Simona Buccolo, Andrea Paccone, Irma Bisceglia, Michelino De Laurentiis
Journal: Journal of Clinical Oncology (2022)

587 Background: The cumulative incidence of cardiac events in breast cancer patients treated with anthracycline and trastuzumab at 1 year after the diagnosis of cancer was 16.4%, at 2 years 23.8 %, and at 3 years 28.2%. Sodium glucose co-transporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality. LCZ696 (neprilysin inhibitor + valsartan) as able to lower the risk of cardiovascular events in chronic heart failure. We hypothesize that dapagliflozin associated to LCZ696 could exerts cardioprotective effects in cellular models of doxorubicin and trastuzumab-induced cardiotoxicity. Methods: Human cardiomyocytes (HL-1 cells) were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin (50 nM) or LCZ696 (at 100 mM) or both in combination for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde, 4-hydroxynonenal and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3 inflammasome, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF were also performed. Results: Dapagliflozin and LCZ696 increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. Combination of dapagliflozin and LCZ696 reduces intracellular Ca2+ overload (-68,4% vs cells treated only to anticancer drugs; p&lt;0,001), lipid peroxidation (mean reduction of 57-63,4 % compared to cells exposed only to anticancer drugs; p&lt;0,05). The expression of MyD88, NLRP3 and NF-kB were strongly reduced after treatment with dapagliflozin and LCZ-696 (-52,5, -43,7 and -57,3 % vs cells exposed only to anticancer drugs, respectively; p&lt;0.05). Notably, combination of dapagliflozin and LCZ-696 enhanced the expression Of IL-10; contrary, pro-inflammatory cytokines were reduced, such as IL-1α, IL-1β, IL-6, IL-8, IL17-α and IL-18 (p&lt;0.05). Conclusions: During exposure to doxorubicin and trastuzumab, dapagliflozin associated to LCZ-696 exerts additive cardioprotective and anti-inflammatory effects compared to each drug alone. Their properties are mediated by the reduction of iCa2+ content that consequently reduces peroxidation and NLRP3- MyD88 expression. These results indicating the potential use of SGLT-2 inhibitors associated to LCZ696 in preclinical models of cardiotoxicity.
Low skeletal muscle area and association with toxicity and hospitalization with chemotherapy in advanced non–small cell lung cancer.
Authors: Anurag Saraf, John He, Kee-Young Shin, Jakob Weiss, Yu-Hui Chen, Paul J. Catalano, Mark M. Awad, David C. Christiani, Hugo Aerts, Raymond H. Mak
Journal: Journal of Clinical Oncology (2022)

8532 Background: Significant toxicity is common in the treatment of advanced non-small cell lung cancer (NSCLC) and can be associated with adverse events, such as unplanned hospitalization, and worse clinical outcomes. Baseline low skeletal muscle (SM) area is a marker of sarcopenia and has been associated with worse survival in other malignancies, but the association of SM area and toxicity in NSCLC is less studied. Methods: Patients with locally advanced or oligo-metastatic NSCLC treated with combined chemotherapy and radiotherapy with or without surgery from 2002-2013 at a single institution were reviewed. A deep-learning pipeline utilized existing pre-treatment computed tomography scans to calculate SM area at the 3rd lumbar vertebral level. Gold standard SM index (SMI) was calculated, adjusting for height, sex, and dichotomized per previously validated cutoff values. Grade 3 or higher hematologic (G3+ heme) toxicity, was assessed per NCI CTCAE v5.0, within 21-days of first chemotherapy cycle. Hospital use was defined as unplanned ED visit or inpatient hospitalization during chemotherapy. Multivariate analysis (MVA) of toxicity endpoints with SMI and baseline characteristics were analyzed by logistic regression analysis, and with overall survival (OS) using Cox regression analysis. Results: A total of 369 patients met inclusion criteria with median follow-up of 23.0mo (range 1-193mo), median age of 64y (range 29-88y), and were mostly male (51%). Most were clinical stage (AJCC 7th edition) IIIA (44%), IIIB (31%), or IV (10%), while 10% had upfront surgery and adjuvant chemotherapy. Most common regimen was cisplatin-based (48%). Median OS was 25.5mo and PFS was 14.0mo. Patients with low SMI were more likely to be younger (median age 70y vs 62y), ECOG performance status (PS) &gt; 0 (74% vs 59%), lower BMI (median BMI 23.3 vs 27.7), and not receive cisplatin-based regimen (35% vs 53%). There was no difference in histology, stage, surgery, or every 3-week (q3w) chemotherapy dosing. On MVA, low SMI was associated with increased risk of G3+ heme toxicity (OR 1.74, p = 0.04) and increased hospital use (OR 1.79, p = 0.04). G3+ heme toxicity was also associated with surgery and q3w dosing, but not age, PS, BMI, or regimen. Hospital use was also associated with BMI, surgery, and cisplatin-based regimen, but not age, PS, or q3w dosing. G3+ heme toxicity (HR 1.48, p &lt; 0.01), older age (HR 1.02, p = 0.02), and stage 4 (HR 3.32, p &lt; 0.01) were associated with worse survival on MVA, but not low SMI (HR 1.25, p = 0.11), PS, BMI, surgery, or regimen. Conclusions: Low SMI predicted higher risk of G3+ toxicity during first cycle of chemotherapy. High-risk patients with low SMI experienced significant adverse events and should be considered for more aggressive symptom management or alternative treatment strategies.
MEDB-08. Inhibition of different mitotic targets demonstrated distinct DNA damage and cell death response in p53-mutant medulloblastoma
Authors: Shiying Huang, Jie-Ling Pan, Sekar Karthik, YuChen Du, Qi Lin, Ching C Lau, Adesina Adekunle, Jack M F Su, Angela Major, M Tarek Elghetany, Kam-Man Hui, Xiaonan Li, Wan-Yee Teo
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: In normal cells, cell cycle is tightly regulated by mitotic proteins to ensure smooth transition through each phase of cell division. Here, we examine two proteins – KIF11, a mitotic kinesin, responsible for assembly and maintenance of mitotic spindle during mitosis; and MELK, a serine/threonine kinase, essential for mitotic progression. Cancer cells can upregulate MELK and KIF11 to promote uncontrolled cell division and protect the cells from apoptotic cell death, leading to tumorigenesis. AIMS: We investigated the response of p53-mutant medulloblastoma (MB) by inhibiting KIF11 and MELK separately to study the effects on cell cycle progression and cell death mechanisms. RESULTS: Cell proliferation was suppressed by inhibition of either KIF11 or MELK in MB, independent of p53-mutant status. Regardless of p53-mutant status, inhibiting KIF11 induced cell cycle arrest at G2/M. In contrast, inhibiting MELK (IC50 dose) induced more prominent G2/M arrest in p53-mutant cells compared to p53-wildtype cells. In p53-mutant MB, arrested cells during MELK inhibition subsequently underwent apoptotic cell death at 24h and 48h. With KIF11 inhibition, p53-mutant cells at 24h were already in necrotic stage. p53-mutant cells reached necrotic stage in a shorter time with KIF11 inhibition than MELK inhibition. On immunoblotting, independent of p53-mutant status, KIF11 inhibition produces more significant increase in DNA damage marker and c-PARP indicative of apoptosis, compared to MELK inhibition. Treatment with KIF11 or MELK inhibitor increased p53 protein expression in p53-wildtype (normal stress response). However, in p53-mutant cells, p53 protein expression decreased post-KIF11-inhibition, but remained unchanged post-MELK inhibition. In-vivo, inhibiting KIF11 was less tolerable in a patient-derived orthotopic xenograft model with p53-mutation. CONCLUSION: Inhibition of either mitotic target KIF11 or MELK, can induce anti-proliferative effects in MB. In p53-mutant MB, DNA damage and cell death response with KIF11-inhibition are more marked.
The comprehensive complication index as a tool for reporting the burden of complications after percutaneous nephrolithotomy: Is it time to leave the Clavien-Dindo classification behind?
Authors: L. Boeri, M. Turetti, C. Silvani, I. Fulgheri, G. Lucignani, C. Bebi, F. Ripa, M. Malfatto, S.P. Zanetti, F. Longo, E. De Lorenzis, G. Albo, E. Montanari
Journal: European Urology (2022)
Associations between reductions in routine care delivery and non-COVID-19-related mortality in people with diabetes in England during the COVID-19 pandemic: a population-based parallel cohort study
Authors: Jonathan Valabhji, Emma Barron, Tessa Gorton, Chirag Bakhai, Partha Kar, Bob Young, Kamlesh Khunti, Naomi Holman, Naveed Sattar, Nicholas J Wareham
Journal: The Lancet Diabetes & Endocrinology (2022)
The iTOP trial: Comparing immediate techniques of oncoplastic surgery with conventional breast surgery in women with breast cancer - A prospective, controlled, single-center study
Authors: Michael Bolliger, Pia Lanmüller, Michael Schuetz, Bernhard Heilig, Amadeus Windischbauer, Raimund Jakesz, Tanja Zehetgruber, Michael Gnant, Andreas Gleiss, Daniela Dörfler, Christian Singer, Rupert Bartsch, Werner Haslik, Giacomo Montagna, Florian Fitzal
Journal: International Journal of Surgery (2022)
Animal Models of Exercise From Rodents to Pythons
Authors: Margaret H. Hastings, Jonathan J. Herrera, J. Sawalla Guseh, Bjarni Atlason, Nicholas E. Houstis, Azrul Abdul Kadir, Haobo Li, Cedric Sheffield, Anand P. Singh, Jason D. Roh, Sharlene M. Day, Anthony Rosenzweig
Journal: Circulation Research (2022)

Acute and chronic animal models of exercise are commonly used in research. Acute exercise testing is used, often in combination with genetic, pharmacological, or other manipulations, to study the impact of these manipulations on the cardiovascular response to exercise and to detect impairments or improvements in cardiovascular function that may not be evident at rest. Chronic exercise conditioning models are used to study the cardiac phenotypic response to regular exercise training and as a platform for discovery of novel pathways mediating cardiovascular benefits conferred by exercise conditioning that could be exploited therapeutically. The cardiovascular benefits of exercise are well established, and, frequently, molecular manipulations that mimic the pathway changes induced by exercise recapitulate at least some of its benefits. This review discusses approaches for assessing cardiovascular function during an acute exercise challenge in rodents, as well as practical and conceptual considerations in the use of common rodent exercise conditioning models. The case for studying feeding in the Burmese python as a model for exercise-like physiological adaptation is also explored.
Polypharmacy and premature aromatase inhibitor (AI) discontinuation in older women with breast cancer.
Authors: Elizabeth Joyce, Kelley M. Kidwell, Vered Stearns, Daniel F. Hayes, Anna Maria Storniolo, Norah Lynn Henry
Journal: Journal of Clinical Oncology (2022)

6568 Background: Treatment with AI therapy for at least five years is recommended to reduce risk of cancer recurrence in postmenopausal women with hormone-positive breast cancer, but up to 50% prematurely discontinue their AI. Prior studies have demonstrated higher rates of nonadherence in older patients. Higher rates of comorbidities are also present in older patients, many of which require treatment with prescription medications. However, in prior studies, the impact of polypharmacy on AI persistence in older women has been variable. We evaluated the relationship between use of prescription and over-the-counter (OTC) medications and AI discontinuation in older women in a randomized controlled trial of AI therapy. Methods: In the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, postmenopausal women with stage 0-III hormone-positive breast cancer were randomized to receive exemestane or letrozole and followed for two years. Prescription medication and OTC supplement usage was prospectively collected. Only enrolled participants at least 65 years of age were included in this analysis. Univariate and multivariable Cox proportional hazards models evaluated the association between baseline prescription medications, OTC medications, initial assigned AI medication, and time to discontinuation of initial AI. Results: 131 women at least 65 years old with baseline medication and OTC supplement information were identified. The average age was 70.4 (SD 5). 58 participants (44%) were randomized to exemestane and 73 (56%) to letrozole. 21% had previously received tamoxifen and 18% received taxane-based chemotherapy. The average number of prescription medications at AI initiation was 4.95, and 127 patients reported taking at least one. The average number of OTC medications was 3.23, and 107 patients reported taking at least one. There was no difference in number of prescription medications or OTC medications by study arm. As previously reported, exemestane was associated with premature discontinuation (HR 1.92 [95%CI 1.06-3.50], p = 0.032). Controlling for AI, the risk of discontinuation decreased by 12% for every additional prescription medication (HR 0.88 [95%CI 0.78-0.99], p = 0.038). OTC medication use was not significantly associated with AI duration. Conclusions: Increased prescription medication usage at AI initiation was associated with decreased risk of premature discontinuation of AI. Further research is needed to evaluate this interaction and identify characteristics that impact AI persistence in older women with breast cancer. Clinical trial information: NCT00228956.
Radical cystectomy in renal transplant recipients: The advantages of the robotic approach
Authors: F. Soria, M. Allasia, A. Marquis, G. Calleris, M. Agnello, A. Giordano, S. Mazzoli, M. De Bellis, M. Rosazza, S. Livoti, B. Lillaz, P. Gontero
Journal: European Urology (2022)
Naturally occurring stable calcium isotope ratios are a novel biomarker of bone calcium balance in chronic kidney disease
Authors: Rukshana Shroff, Alexander D. Lalayiannis, Mary Fewtrell, Claus Peter Schmitt, Aysun Bayazit, Varvara Askiti, Augustina Jankauskiene, Justine Bacchetta, Selmy Silva, Nadine Goodman, Louise McAlister, Lorenzo Biassoni, Nicola Crabtree, Anja Rahn, Dagmar-Christiane Fischer, Alexander Heuser, Ana Kolevica, Anton Eisenhauer
Journal: Kidney International (2022)

Dysregulated calcium homeostasis is common in chronic kidney disease and causally associated with disorders of bone mineralization. However, radiological measures and biomarkers do not allow accurate evaluation of bone calcium balance. Non-radioactive calcium isotopes, 42Ca and 44Ca, are present in our diet and sequestered into body compartments following principles of kinetic isotope fractionation. Isotopically light 42Ca is preferentially incorporated into bone, while heavier 44Ca is excreted. The ratio (44/42Caserum) increases when bone formation exceeds resorption and vice versa, reflecting bone calcium balance. We measured these calcium isotopes by inductively coupled plasma mass-spectrometry in blood, urine and feces of 42 children with chronic kidney disease and 92 receiving dialysis therapy. We compared the isotope ratios with bone biomarkers and determined total bone mineral content by dual-energy x-ray absorptiometry and peripheral quantitative CT expressed as age-adjusted z-scores. The 44/42Caserum ratio positively correlated with serum calcium, 25-hydroxyvitamin D and alkaline phosphatases and inversely with serum parathyroid hormone and other bone resorption markers. The 44/42Caserum ratio positively correlated with age-adjusted z-scores of tibial trabecular bone mineral density and total bone mineral content measured by peripheral quantitative CT, and hip bone mineral density measured by dual-energy X-ray absorptiometry. Significant and independent predictors of total bone mineral content, measured by, were the 44/42Caserum ratio and parathyroid hormone. The 44/42Caserum ratio, repeated after four weeks, highly correlated with baseline values. When adjusted for calcium-containing medications and kidney impairment, the 44/42Caserum ratio in patients receiving dialysis was 157% lower than that of age-matched children and 29% lower than levels in elderly women with osteoporosis, implying significantly lower bone mineral content. Thus, calcium isotope ratios may provide a novel, sensitive and non-invasive method of assessing bone calcium balance in chronic kidney disease.
Extended neoadjuvant therapy in NSCLC achieved remarkable pathological complete response (pCR) rate and prolonged disease-free survival.
Authors: Zhaohui Fan, Xiaojunn Wang, Youtao Xu, Si Li, Dong-sheng Chen, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2022)

e20500 Background: Over 50% early stage NSCLC patients would suffer from recurrence and distant metastasis. Neoadjuvant TKI therapy had been explored aiming to reduce recurrence and metastasis. Erlotinib neoadjuvant therapy (NAT) significantly improved ORR, PFS and major pathologic response (MPR) rate in trial EMERGING/CTONG1103. In our hospital, some patients received extended neoadjuvant treatment because of continued lesion remission. These patients eventually received surgery when the lesions stopped remission and achieved remarkable pathologically complete remission (pCR) rate. Herein we analyzed the efficacy of extended NAT. Methods: 9 NSCLC patients who received extended neoadjuvant therapy in Department of Thoracic Surgery, Jiangsu Cancer Hospital from 2013-2020 were enrolled in this study. Extended neoadjuvant therapy was defined as duration of treatment longer than standard regimens (for TKI, longer than 42 days; for chemotherapy, longer than 2 cycles or 6 weeks). Pathological complete response, progression free survival (PFS), overall survival (OS) were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Standard statistical methods, including descriptive statistics, x2 test, two-sided 95% CI were used. Results: Up to 9 patients were enrolled in this study. There were 5 patients in TKI group, 1 (20%) was male and 4 (80%) were female. There were 4 patients in chemo group, 2 (50%) were male and 2 (50%) were female. The median age of TKI and chemotherapy groups were 59 (47-70) and 62 (30-75), respectively. The median duration of treatment (DOT) were 185 (163-248) and 82 (29-98) days, respectively. Among TKI group, 4 patients were EGFR L858R positive and 1 was ALK rearrangement positive and they all received relative TKI treatment based on genetic feature. In the TKI group, all 5 patients achieved pCR, the pCR rate was 100%. In chemotherapy group, 1 out of 4 patients achieved pCR and the other 3 achieved major pathological response (MPR). The pCR rate was 25% and MPR rate was 100%. The pCR rate of TKI group was significantly higher than chemotherapy group (100% vs 25%, p &lt; 0.01). The pCR rate or MPR rate was higher than historical data. For instance, in trial CTONG 1103, neither TKI (Erlotininb) or chemotherapy (Gemcitabine) group achieved pCR, and the MPR rate was only 45% in TKI group and 51% in chemotherapy group. Extended NAT regimen in our study achieved much higher pCR rate (100% vs 0% for TKI and 25% vs 0% for chemotherapy) and MPR rate (100% vs 45%̃51%) than standard 42 days regimens used in CTONG-1103. Conclusions: Extended NAT resulted in better pCR rate and MPR rate than the standard 42-days duration of NAT. For patients with good response to TKI in the neoadjuvant stage, extending the duration neoadjuvant TKI treatment until lesions stopped remission might result in better pCR rate and might extend PFS and OS.
MODL-23. The identification and validation of plasma membrane proteins as potential therapeutic targets for histone H3 mutant paediatric high-grade gliomas.
Authors: Anya Snary, James Pickering, Ruman Rahman, Richard Grundy, Farhana Haque, Robert Layfield
Journal: Neuro-Oncology (2022)

Abstract Paediatric high grade gliomas (pHGG) are the leading cause of cancer-related death in children. Histone H3.3 mutations are an important hallmark of pHGG, but their underlying oncogenic mechanisms are incompletely understood. Towards identifying molecular effectors that may be therapeutically effective, we employed proteomic profiling and determined plasma membrane proteins of the surfactome that are differentially expressed on the surface of H3.3 mutant (G34R, G34V) compared to H3.3-wildtype human glioma cells in culture. Profiling of plasma membrane-enriched fractions identified 34 membrane proteins exclusively detected from H3 G34V mutant cells compared to H3 wild-type cells, and 10 membrane proteins exclusively detected from H3 G34R mutant cells, with 39 membrane proteins shared between both H3 G34R/V genotypes. One of these shared membrane proteins, GLUT1 (glucose transporter), has very recently been reported to be over-expressed and linked to tumour phenotypes in mouse glioma cells manipulated to carry the most common DIPG-associated H3.3-K27M mutation [Miya et al. Neuro-Oncology Advances 2021]. Here, we explore the functional significance of GLUT1 differential expression in H3.3 mutant (G34R, G34V) human glioma cells. Collective observations support a model where different H3.3 mutations converge on changes in GLUT1 expression and reinforce GLUT1 as a potential therapeutic target in paediatric high-grade gliomas.
Online public interest in urological cancers during the Covid-19 pandemic: What can “Dr. Google” teach us?
Authors: Z-E. Khene, S. Guérin, F. Khene, B. Pradère, M. Roumiguié, R. Mathieu, L. Albiges, D. Borchiellini, G. Pignot, Y. Neuzillet, G. Ploussard, P. Bigot, A. De La Taille, M. Rouprêt, K. Bensalah
Journal: European Urology (2022)